Acetaminophen (APAP) is a well established therapeutic agent having both analgesic and antipyretic activity. Acetaminophen's relatively poor solubility in water and its bitter taste, however, make it difficult to formulate into to consumer acceptable oral dosage forms. Most commercially available acetaminophen oral dosage forms incorporate a taste masking coating on the acetaminophen particles or employ flavors and sweeteners to mask the bitter taste of the drug.
Other approaches for dealing with the solubility and taste of acetaminophen include the formation of amino acid esters of acetaminophen. I. M. Kovach in Diss. Abstr. Int. B 1975, 36(2), 734-5 describes the synthesis of p-acetamidophenyl glycinate (APG), .alpha.-p-acetamidophenyl aspartate (AAPA) and .beta.-p-acetamidophenyl aspartate (BAPA). These esters are reported to have a less bitter taste than acetaminophen. APG-HBr was five times more water soluble than acetaminophen, whereas BAPA-HCl was four times less water soluble than APAP.
It is also known that the formation of an appropriate salt of a hydrophobic compound, such as a lipophilic carboxylic acid, will usually improve the aqueous solubility of the compound. Sodium ibuprofen and sodium naproxen are examples of pharmaceutically active lipophilic carboxylic acids which have improved aqueous solubility in their salt form. These salts are typically formed by reacting the carboxylic acid with a strong base, such as sodium hydroxide or potassium hydroxide.
USSR Inventor's Certificate No. 629,209, published Sep. 11, 1978, describes a method of preparing bis-[.beta.-(4-acetylaminophenyloxy)ethyl]ether by reacting 4-acetylaminophenol with an alkaline agent, such as potassium hydroxide, in a solution of an organic solvent, such as dimethylformamide, followed by reacting the resulting solution of potassium phenolate with chlorex at the boiling point of the reaction mixture. The resulting ether is reported as being useful for the treatment of animals with helminthic diseases.
USSR Inventor's Certificate 1,803,833, published Mar 23, 1993, describes a method of preparing acetaminophen for fluorescence intensity measurements. The acetaminophen sample was prepared by first dissolving in isopropyl alcohol and then treating with an 8% solution of potassium hydroxide solution and chloroform at a KOH:chloroform volume ratio of 3-4. Heating was then carried out for 15-20 minutes at 70-80.degree. C. before the measurement of the sample's fluorescence intensity.
While both of the of the above-identified USSR Inventor's Certificates report the treatment of acetaminophen with potassium hydroxide, neither document reports the isolation of any potassium salt of acetaminophen.
M. S. Yu et al. in U.S. Pat. No. 5,360,615 discusses a pharmaceutical carrier system for enhancing the solubility of acidic, basic or amphoteric pharmaceuticals by partial ionization to produce a highly concentrated primarily non-aqueous solution suitable for filling softgels or for two-piece encapsulation or tablet formation. The acetaminophen solution comprised 25-40% (wt.) of acetaminophen, 0.4-1.0 moles of hydroxide ion per mole of acetaminophen and 1-20% (wt.) water in polyethylene glycol. An exemplary concentrated solution of acetaminophen suitable for use as a softgel fill contained 1 equivalent APAP (35% by wt.), 1 equivalent potassium hydroxide, and the balance polyethylene glycol 600.
U.S. Pat. No. 5,273,759 to D. L. Simmons describes the addition of Mg(OH).sub.2 in solid form to tablets containing APAP.
Both Yu et al. and Simmons fail to report the isolation of any discrete salts of acetaminophen.
A need exists for isolated salts of acetaminophen with improved aqueous solubility and taste when compared to the conventional form of acetaminophen.